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3. CHAMP1-related disorders: pathomechanisms triggered by different genomic alterations define distinct nosological categories

Author

Amenta, Simona, Marangi, Giuseppe, Orteschi, D., Frangella, Silvia, Gurrieri, Fiorella, Paccagnella, E., Torella, A., Cappuccio, G., Musacchia, F., Mutarelli, Massimiano, Carrella, D., Vitiello, G., Parenti, Gian Paolo, Leuzzi, V., Selicorni, A., Maitz, S., Brunetti-Pierri, N., Banfi, S., Montomoli, M., Milani, Daniela, Romano, Maria Concetta, Tummolo, Aida Angela, De Brasi, D., Coppola, A., Santoro, C., Scala, M., Romano, Federica, Capra, V., Nigro, V., Zollino, Marcella, Amenta S., Marangi G. (ORCID:0000-0002-6898-8882), Frangella S., Gurrieri F. (ORCID:0000-0002-6775-5972), Mutarelli M., Parenti G., Milani D., Romano C., Tummolo A., Romano F., Zollino M. (ORCID:0000-0003-4871-9519), Amenta, Simona, Marangi, Giuseppe, Orteschi, D., Frangella, Silvia, Gurrieri, Fiorella, Paccagnella, E., Torella, A., Cappuccio, G., Musacchia, F., Mutarelli, Massimiano, Carrella, D., Vitiello, G., Parenti, Gian Paolo, Leuzzi, V., Selicorni, A., Maitz, S., Brunetti-Pierri, N., Banfi, S., Montomoli, M., Milani, Daniela, Romano, Maria Concetta, Tummolo, Aida Angela, De Brasi, D., Coppola, A., Santoro, C., Scala, M., Romano, Federica, Capra, V., Nigro, V., Zollino, Marcella, Amenta S., Marangi G. (ORCID:0000-0002-6898-8882), Frangella S., Gurrieri F. (ORCID:0000-0002-6775-5972), Mutarelli M., Parenti G., Milani D., Romano C., Tummolo A., Romano F., and Zollino M. (ORCID:0000-0003-4871-9519)

Abstract

Loss-of-function variants in CHAMP1 were recently described as cause of a neurodevelopmental disorder characterized by intellectual disability (ID), autism, and distinctive facial characteristics. By exome sequencing (ES), we identified a truncating variant in CHAMP1, c.1858A > T (p.Lys620*), in a patient who exhibited a similar phenotype of severe ID and dysmorphisms. Whether haploinsufficiency or a dominant negative effect is the underlying pathomechanism in these cases is a question that still needs to be addressed. By array-CGH, we detected a 194 kb deletion in 13q34 encompassing CHAMP1, CDC16 and UPF3, in another patient who presented with borderline neurodevelopmental impairment and with no dysmorphisms. In a further patient suffering from early onset refractory seizures, we detected by ES a missense variant in CHAMP1, c.67 G > A (p.Gly23Ser). Genomic abnormalities were all de novo in our patients. We reviewed the clinical and the genetic data of patients reported in the literature with: loss-of-function variants in CHAMP1 (total 40); chromosome 13q34 deletions ranging from 1.1 to 4 Mb (total 7) and of the unique patient with a missense variant. We could infer that loss-of-function variants in CHAMP1 cause a homogeneous phenotype with severe ID, autism spectrum disorders (ASD) and highly distinctive facial characteristics through a dominant negative effect. CHAMP1 haploinsufficiency results in borderline ID with negligible consequences on the quality of life. Missense variants give rise to a severe epileptic encephalopathy through gain-of-function mechanism, most likely. We tentatively define for the first time distinct categories among the CHAMP1-related disorder on the basis of pathomechanisms.

Published
2023

4. Diagnostic issues faced by a rare disease healthcare network during Covid-19 outbreak: data from the Campania Rare Disease Registry

Author

Limongelli G, Iucolano S, Monda E, Elefante P, De Stasio C, Lubrano I, Caiazza M, Mazzella M, Fimiani F, Galdo M, De Marchi G, Esposito M, Rubino M, Cirillo A, Fusco A, Esposito A, Trama U, Esposito S, Scarano G, Sepe J, Andria G, Orlando V, Menditto E, Chiodini P, Campania Rare Disease, Iolascon A, Franzese A, Sanduzzi Zamparelli A, Tessitore A, Romano A, Venosa A, Nunzia Olivieri A, Bianco A, La Manna A, Cerbone AM, Spasiano A, Agnese Stanziola A, Colao A, De Bellis A, Gambale A, Toriello A, Tufano A, Ciampa A, Maria Risitano A, Pisani A, Russo A, Volpe A, De Martino B, Amato B, De Fusco C, Piscopo C, Selleri C, Tucci C, Pignata C, Cioffi D, Melis D, Pasquali D, De Brasi D, Spitaleri D, Russo D, Martellotta D, De Michele E, Varricchio E, Miraglia Del Giudice E, Coscioni E, Cimino E, Pane F, Tranfa F, Pollio F, Lonardo F, Nuzzi F, Simonelli F, Trojsi F, Habetswallner F, Valentini G, Cerbone G, Parenti G, Tedeschi G, Capasso G, Battista Rossi G, Gaglione G, Sarnelli G, Argenziano G, Bellastella G, De Michele G, Fiorentino G, Spadaro G, Scala I, Santoro L, Zeppa L, Auricchio L, Elio Adinolfi L, Alessio M, Amitrano M, Savanelli MC, Russo MG, Ferrucci MG, Carbone MT, Pellecchia MT, Salerno M, Melone M, Del Donno M, Vitale M, Triggiani M, Della Monica M, Lo Presti M, Tenuta M, Mignogna MD, Schiavulli M, Zacchia M, Brunetti-Pierri N, Iovino P, Moscato P, Iandoli R, Scarpa R, Russo R, Troisi S, Sbordone S, Perrotta S, Fecarotta S, Sampaolo S, Cicalese V., Limongelli, Giuseppe, Iucolano, Stefano, Monda, Emanuele, Elefante, Pasquale, De Stasio, Chiara, Lubrano, Imma, Caiazza, Martina, Mazzella, Marialuisa, Fimiani, Fabio, Galdo, Maria, De Marchi, Giulia, Esposito, Martina, Rubino, Marta, Cirillo, Annapaola, Fusco, Adelaide, Esposito, Augusto, Trama, Ugo, Esposito, Salvatore, Scarano, Gioacchino, Sepe, Joseph, Andria, Generoso, Orlando, Valentina, Menditto, Enrica, Chiodini, Paolo, Iolascon, Achille, Franzese, Adriana, Sanduzzi Zamparelli, Alessandro, Tessitore, Alessandro, Romano, Alfonso, Venosa, Alfredo, Nunzia Olivieri, Alma, Bianco, Andrea, La Manna, Angela, Cerbone, Anna Maria, Spasiano, Anna, Agnese Stanziola, Anna, Colao, Annamaria, De Bellis, Annamaria, Gambale, Antonella, Toriello, Antonella, Tufano, Antonella, Ciampa, Antonio, Maria Risitano, Antonio, Pisani, Antonio, Russo, Antonio, Volpe, Antonio, De Martino, Bernardo, Amato, Bruno, De Fusco, Carmela, Piscopo, Carmelo, Selleri, Carmine, Tucci, Celeste, Pignata, Claudio, Cioffi, Daniela, Melis, Daniela, Pasquali, Daniela, De Brasi, Daniele, Spitaleri, Daniele, De Brasi, Davide, Russo, Domenico, Martellotta, Donata, De Michele, Elisa, Varricchio, Elziario, Miraglia Del Giudice, Emanuele, Coscioni, Enrico, Cimino, Ernesto, Pane, Fabrizio, Tranfa, Fausto, Pollio, Filiberto, Lonardo, Fortunato, Nuzzi, Francesca, Simonelli, Francesca, Trojsi, Francesca, Habetswallner, Francesco, Valentini, Gabriele, Cerbone, Gaetana, Parenti, Giancarlo, Tedeschi, Gioacchino, Capasso, Giovambattista, Battista Rossi, Giovanni, Gaglione, Giovanni, Sarnelli, Giovanni, Argenziano, Giuseppe, Bellastella, Giuseppe, De Michele, Giuseppe, Fiorentino, Giuseppe, Spadaro, Giuseppe, Scala, Iri, Santoro, Lucio, Zeppa, Lucio, Auricchio, Luigi, Elio Adinolfi, Luigi, Alessio, Maria, Amitrano, Maria, Savanelli, Maria Cristina, Russo, Maria Giovanna, Ferrucci, Maria Grazia, Carbone, Maria Teresa, Pellecchia, Maria Teresa, Salerno, Mariacarolina, Melone, Marina, Del Donno, Mario, Vitale, Mario, Triggiani, Massimo, Della Monica, Matteo, Lo Presti, Maurizio, Tenuta, Maurizio, Mignogna, Michele Davide, Schiavulli, Michele, Zacchia, Miriam, Brunetti-Pierri, Nicola, Iovino, Paola, Moscato, Paolo, Iandoli, Raffaele, Scarpa, Raffaele, Russo, Romualdo, Troisi, Salvatore, Sbordone, Sandro, Perrotta, Silverio, Fecarotta, Simona, Sampaolo, Simone, Cicalese, Virgilio, Limongelli, G, Iucolano, S, Monda, E, Elefante, P, De Stasio, C, Lubrano, I, Caiazza, M, Mazzella, M, Fimiani, F, Galdo, M, De Marchi, G, Esposito, M, Rubino, M, Cirillo, A, Fusco, A, Esposito, A, Trama, U, Esposito, S, Scarano, G, Sepe, J, Andria, G, Orlando, V, Menditto, E, Chiodini, P, Campania Rare, Disease, Iolascon, A, Franzese, A, Sanduzzi Zamparelli, A, Tessitore, A, Romano, A, Venosa, A, Nunzia Olivieri, A, Bianco, A, La Manna, A, Cerbone, Am, Spasiano, A, Agnese Stanziola, A, Colao, A, De Bellis, A, Gambale, A, Toriello, A, Tufano, A, Ciampa, A, Maria Risitano, A, Pisani, A, Russo, A, Volpe, A, De Martino, B, Amato, B, De Fusco, C, Piscopo, C, Selleri, C, Tucci, C, Pignata, C, Cioffi, D, Melis, D, Pasquali, D, De Brasi, D, Spitaleri, D, Russo, D, Martellotta, D, De Michele, E, Varricchio, E, Miraglia Del Giudice, E, Coscioni, E, Cimino, E, Pane, F, Tranfa, F, Pollio, F, Lonardo, F, Nuzzi, F, Simonelli, F, Trojsi, F, Habetswallner, F, Valentini, G, Cerbone, G, Parenti, G, Tedeschi, G, Capasso, G, Battista Rossi, G, Gaglione, G, Sarnelli, G, Argenziano, G, Bellastella, G, De Michele, G, Fiorentino, G, Spadaro, G, Scala, I, Santoro, L, Zeppa, L, Auricchio, L, Elio Adinolfi, L, Alessio, M, Amitrano, M, Savanelli, Mc, Russo, Mg, Ferrucci, Mg, Carbone, Mt, Pellecchia, Mt, Salerno, M, Melone, M, Del Donno, M, Vitale, M, Triggiani, M, Della Monica, M, Lo Presti, M, Tenuta, M, Mignogna, Md, Schiavulli, M, Zacchia, M, Brunetti-Pierri, N, Iovino, P, Moscato, P, Iandoli, R, Scarpa, R, Russo, R, Troisi, S, Sbordone, S, Perrotta, S, Fecarotta, S, Sampaolo, S, and Cicalese, V.

Subjects
Pediatrics, medicine.medical_specialty, Coronavirus disease 2019 (COVID-19), Home therapy, rare diseases, 030204 cardiovascular system & hematology, Campania region, Covid-19, Italy, patient registry, Disease Outbreaks, 03 medical and health sciences, COVID-19 Testing, 0302 clinical medicine, Pandemic, Health care, medicine, Retrospective analysis, Humans, AcademicSubjects/MED00860, Registries, 030212 general & internal medicine, Medical diagnosis, Pandemics, Retrospective Studies, business.industry, Public Health, Environmental and Occupational Health, Outbreak, General Medicine, Original Article, business, Delivery of Health Care, Rare disease
Abstract

Background The aims of this study were: to investigate the capacity of the rare disease healthcare network in Campania to diagnose patients with rare diseases during the outbreak of Covid-19; and to shed light on problematic diagnoses during this period. Methods To describe the impact of the Covid-19 pandemic on the diagnosis of patients with rare diseases, a retrospective analysis of the Campania Region Rare Disease Registry was performed. A tailored questionnaire was sent to rare disease experts to investigate major issues during the emergency period. Results Prevalence of new diagnoses of rare disease in March and April 2020 was significantly lower than in 2019 (117 versus 317, P Conclusions This study describes the effects of the Covid-19 outbreak on the diagnosis of rare disease in a single Italian region and investigates potential issues of diagnosis and management during this period.

Published
2021

5. Integrated exome and transcriptome analysis prioritizes MAP4K4 de novo frameshift variants in autism spectrum disorder as a novel disease–gene association

Author

Cesana, M., primary, Vaccaro, L., additional, Larsen, M. J., additional, Kibæk, M., additional, Micale, L., additional, Riccardo, S., additional, Annunziata, P., additional, Colantuono, C., additional, Di Filippo, L., additional, De Brasi, D., additional, Castori, M., additional, Fagerberg, C., additional, Acquaviva, F., additional, and Cacchiarelli, D., additional

Published
2022
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6. Endocrine system involvement in patients with RASopathies: A case series

Author

Siano, M. A., primary, Pivonello, R., additional, Salerno, M., additional, Falco, M., additional, Mauro, C., additional, De Brasi, D., additional, Klain, A., additional, Sestito, S., additional, De Luca, A., additional, Pinna, V., additional, Simeoli, C., additional, Concolino, D., additional, Mainolfi, Ciro Gabriele, additional, Mannarino, T., additional, Strisciuglio, P., additional, Tartaglia, M., additional, and Melis, D., additional

Published
2022
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7. Variant-specific changes in RAC3 function disrupt corticogenesis in neurodevelopmental phenotypes

Author

Scala, M., Nishikawa, M., Ito, H., Tabata, H., Khan, T., Accogli, A., Davids, L., Ruiz, A., Chiurazzi, Pietro, Cericola, G., Schulte, B., Monaghan, K. G., Begtrup, A., Torella, A., Pinelli, M., Denomme-Pichon, A. -S., Vitobello, A., Racine, C., Mancardi, M. M., Kiss, C., Guerin, A., Wu, W., Vila, E. G., Mak, B. C., Martinez-Agosto, J. A., Gorin, M. B., Duz, B., Bayram, Y., Carvalho, C. M. B., Vengoechea, J. E., Chitayat, D., Tan, T. Y., Callewaert, B., Kruse, B., Bird, L. M., Faivre, L., Zollino, Marcella, Biskup, S., Striano, P., Nigro, V., Severino, M., Capra, V., Costain, G., Nagata, K. -I., Brown, G., Butte, M. J., Dell'Angelica, E. C., Dorrani, N., Douine, E. D., Fogel, B. L., Gutierrez, I., Huang, A., Krakow, D., Lee, H., Loo, S. K., Martin, M. G., Mcgee, E., Nelson, S. F., Nieves-Rodriguez, S., Palmer, C. G. S., Papp, J. C., Parker, N. H., Renteria, G., Sinsheimer, J. S., Wan, J., Wang, L. -K., Perry, K. W., Brunetti-Pierri, N., Casari, G., Cappuccio, G., Musacchia, F., Mutarelli, M., Carrella, D., Vitiello, G., Parenti, G., Leuzzi, V., Selicorni, A., Maitz, S., Banfi, S., Montomoli, M., Milani, D., Romano, C., Tummolo, A., De Brasi, D., Coppola, A., Santoro, C., Peron, A., Pantaleoni, C., Castello, R., D'Arrigo, S., Scala, Marcello, Nishikawa, Masashi, Ito, Hidenori, Tabata, Hidenori, Khan, Tayyaba, Accogli, Andrea, Davids, Laura, Ruiz, Anna, Chiurazzi, Pietro, Cericola, Gabriella, Schulte, Björn, Monaghan, Kristin G, Begtrup, Amber, Torella, Annalaura, Pinelli, Michele, Denommé-Pichon, Anne Sophie, Vitobello, Antonio, Racine, Caroline, Mancardi, Maria Margherita, Kiss, Courtney, Guerin, Andrea, Wu, Wendy, Gabau Vila, Elisabeth, Mak, Bryan C, Martinez-Agosto, Julian A, Gorin, Michael B, Duz, Bugrahan, Bayram, Yavuz, Carvalho, Claudia M B, Vengoechea, Jaime E, Chitayat, David, Tan, Tiong Yang, Callewaert, Bert, Kruse, Bernd, Bird, Lynne M, Faivre, Laurence, Zollino, Marcella, Biskup, Saskia, Striano, Pasquale, Nigro, Vincenzo, Severino, Mariasavina, Capra, Valeria, Costain, Gregory, Nagata, Koh Ichi, and Nagata, Koh-Ichi

Subjects
brain development, Settore MED/03 - GENETICA MEDICA, Medical and Health Sciences, Telethon Undiagnosed Diseases Program, Mice, Neurodevelopmental Disorder, Medicine and Health Sciences, Animals, Humans, 2.1 Biological and endogenous factors, Aetiology, Neurons, Pediatric, neuronal migration, Neurology & Neurosurgery, Animal, axon guidance, Psychology and Cognitive Sciences, p21-Activated Kinase, Neurosciences, Biology and Life Sciences, Undiagnosed Diseases Network, Neuron, rac GTP-Binding Proteins, Brain Disorders, RAC3, Phenotype, p21-Activated Kinases, Neurodevelopmental Disorders, small GTPase, Neurological, Congenital Structural Anomalies, Neurology (clinical), Human
Abstract

Variants in RAC3, encoding a small GTPase RAC3 which is critical for the regulation of actin cytoskeleton and intracellular signal transduction, are associated with a rare neurodevelopmental disorder with structural brain anomalies and facial dysmorphism. We investigated a cohort of 10 unrelated participants presenting with global psychomotor delay, hypotonia, behavioural disturbances, stereotyped movements, dysmorphic features, seizures and musculoskeletal abnormalities. MRI of brain revealed a complex pattern of variable brain malformations, including callosal abnormalities, white matter thinning, grey matter heterotopia, polymicrogyria/dysgyria, brainstem anomalies and cerebellar dysplasia. These patients harboured eight distinct de novo RAC3 variants, including six novel variants (NM_005052.3): c.34G > C p.G12R, c.179G > A p.G60D, c.186_188delGGA p.E62del, c.187G > A p.D63N, c.191A > G p.Y64C and c.348G > C p.K116N. We then examined the pathophysiological significance of these novel and previously reported pathogenic variants p.P29L, p.P34R, p.A59G, p.Q61L and p.E62K. In vitro analyses revealed that all tested RAC3 variants were biochemically and biologically active to variable extent, and exhibited a spectrum of different affinities to downstream effectors including p21-activated kinase 1. We then focused on the four variants p.Q61L, p.E62del, p.D63N and p.Y64C in the Switch II region, which is essential for the biochemical activity of small GTPases and also a variation hot spot common to other Rho family genes, RAC1 and CDC42. Acute expression of the four variants in embryonic mouse brain using in utero electroporation caused defects in cortical neuron morphology and migration ending up with cluster formation during corticogenesis. Notably, defective migration by p.E62del, p.D63N and p.Y64C were rescued by a dominant negative version of p21-activated kinase 1. Our results indicate that RAC3 variants result in morphological and functional defects in cortical neurons during brain development through variant-specific mechanisms, eventually leading to heterogeneous neurodevelopmental phenotypes. Scala et al. identify six de novo variants in RAC3, which encodes a small GTPase, in 10 unrelated subjects with neurodevelopmental phenotypes. In vivo and in vitro analyses in mice reveal that RAC3 variants cause morpho-functional defects in cortical neurons through variant-specific mechanisms, disrupting corticogenesis.

Published
2022

9. Additional file 1 of Risk of autoimmune diseases in patients with RASopathies: systematic study of humoral and cellular immunity

Author

Siano, M. A., Marchetti, V., Pagano, S., Di Candia, F., Alessio, M., De Brasi, D., De Luca, A., Pinna, V., Sestito, S., Concolino, D., Tartaglia, M., Strisciuglio, P., D’Esposito, V., Cabaro, S., Perruolo, G., Formisano, P., and Melis, D.

Abstract

Additional file 1: Table S1. Patients immunoglobulin values compared to normal values for age. Table S2. Patients lymphocyte subpopulations values compared to normal values for age. Normal values are reported as mean (10th and 90th percentile). Taken from Shearer et al, JACI 2003.

Published
2021
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10. Milder presentation of TELO2-related syndrome in two sisters homozygous for the p.Arg609His pathogenic variant

Author

Ciaccio, C., Duga, V., Pantaleoni, C., Esposito, S., Moroni, I., Pinelli, M., Castello, R., Nigro, V., Chiapparini, L., D'Arrigo, S., Torella, A., Cappuccio, G., Musacchia, F., Mutarelli, M., Carrella, D., Vitiello, G., Parenti, G., Capra, V., Leuzzi, V., Selicorni, A., Maitz, S., Brunetti-Pierri, N., Banfi, S., Zollino, Marcella, Montomoli, M., Milani, D., Romano, C., Tummolo, A., De Brasi, D., Coppola, A., Santoro, C., Zollino M. (ORCID:0000-0003-4871-9519), Ciaccio, C., Duga, V., Pantaleoni, C., Esposito, S., Moroni, I., Pinelli, M., Castello, R., Nigro, V., Chiapparini, L., D'Arrigo, S., Torella, A., Cappuccio, G., Musacchia, F., Mutarelli, M., Carrella, D., Vitiello, G., Parenti, G., Capra, V., Leuzzi, V., Selicorni, A., Maitz, S., Brunetti-Pierri, N., Banfi, S., Zollino, Marcella, Montomoli, M., Milani, D., Romano, C., Tummolo, A., De Brasi, D., Coppola, A., Santoro, C., and Zollino M. (ORCID:0000-0003-4871-9519)

Abstract

Biallelic loss of function of TELO2 gene cause a severe syndromic disease mainly characterized by global developmental delay with poor motor and language acquisitions, microcephaly, short stature, minor facial and limbs anomalies, sleep disorder, spasticity, and balance impairment up to ataxia. TELO2-related syndrome, also known as You-Hoover-Fong Syndrome, is extremely rare and since its first description in 2016 only 8 individuals have been reported, all showing a severe disability. The causative gene is member of the big molecular family of genes responsible for cells proliferation and DNA stability. We describe the case of two sisters, carrying the homozygous p. Arg609His variant of the gene, who present a milder phenotype of TELO2-related syndrome. Such variant has been reported once in a more severely affected patient, in compound heterozygous state associated with the p. Pro260Leu variant, suggesting a possible role of the p. Arg609His variant in determining milder phenotypes. Comparing the siblings with all previously reported cases, we offer an overview on the condition and discuss TELO2 genetic interactions, in order to further explore the molecular bases of this recently described disorder.

Published
2021

11. Consolidating the Role of TDP2 Mutations in Recessive Spinocerebellar Ataxia Associated with Pediatric Onset Drug Resistant Epilepsy and Intellectual Disability (SCAR23)

Author

Ciaccio C., Castello R., Esposito S., Pinelli M., Nigro V., Casari G., Chiapparini L., Pantaleoni C., Torella A., Cappuccio G., Musacchia F., Mutarelli M., Carrella D., Vitiello G., Parenti G., Capra V., Leuzzi V., Selicorni A., Maitz S., Brunetti-Pierri N., Banfi S., Zollino M., Montomoli M., Milani D., Romano C., Tummolo A., De Brasi D., Coppola A., Santoro C., D'Arrigo S., Ciaccio, C., Castello, R., Esposito, S., Pinelli, M., Nigro, V., Casari, G., Chiapparini, L., Pantaleoni, C., Torella, A., Cappuccio, G., Musacchia, F., Mutarelli, M., Carrella, D., Vitiello, G., Parenti, G., Capra, V., Leuzzi, V., Selicorni, A., Maitz, S., Brunetti-Pierri, N., Banfi, S., Zollino, M., Montomoli, M., Milani, D., Romano, C., Tummolo, A., De Brasi, D., Coppola, A., Santoro, C., D'Arrigo, S., Ciaccio, Claudia, Castello, Raffaele, Esposito, Silvia, Pinelli, Michele, Nigro, Vincenzo, Casari, Giorgio, Chiapparini, Luisa, Pantaleoni, Chiara, and D'Arrigo, Stefano

Subjects
Drug Resistant Epilepsy, medicine.medical_specialty, Pediatrics, Neurology, Ataxia, Adolescent, SCAR23, Disease, Whole Exome Sequencing, 050105 experimental psychology, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Intellectual Disability, Exome Sequencing, Intellectual disability, Humans, Spinocerebellar Ataxias, Medicine, 0501 psychology and cognitive sciences, TDP2, Phosphoric Diester Hydrolases, business.industry, 05 social sciences, Pediatric ataxia, medicine.disease, DNA-Binding Proteins, Mutation, Cerebellar atrophy, Spinocerebellar ataxia, Female, Neurology (clinical), medicine.symptom, business, 030217 neurology & neurosurgery
Abstract

Spinocerebellar Ataxia 23 (SCAR23) is a newly described condition caused by mutations in TDP2 gene. To date, only four patients from two families have been reported, all carrying the same homozygous mutation. We describe a fifth patient, carrying a novel mutation in the same gene, thus confirming the role of TDP2 mutations in determining the disease and defining the main features SCAR23: pediatric onset ataxia and drug-resistant epilepsy and intellectual disability. We further show the clinical presentation which is associated with the neuroradiological evidence of progressive cerebellar atrophy, giving the evidence that SCAR23 can be classified as a degenerative condition.

Published
2019

12. De novo SMARCA2 variants clustered outside the helicase domain cause a new recognizable syndrome with intellectual disability and blepharophimosis distinct from Nicolaides–Baraitser syndrome

Author

Cappuccio, G., Sayou, C., Tanno, P. L., Tisserant, E., Bruel, A. -L., Kennani, S. E., Sa, J., Low, K. J., Dias, C., Havlovicova, M., Hancarova, M., Eichler, E. E., Devillard, F., Moutton, S., Van-Gils, J., Dubourg, C., Odent, S., Gerard, B., Piton, A., Yamamoto, T., Okamoto, N., Firth, H., Metcalfe, K., Moh, A., Chapman, K. A., Aref-Eshghi, E., Kerkhof, J., Torella, A., Nigro, V., Perrin, L., Piard, J., Le Guyader, G., Jouan, T., Thauvin-Robinet, C., Duffourd, Y., George-Abraham, J. K., Buchanan, C. A., Williams, D., Kini, U., Wilson, K., Brunetti-Pierri, N., Casari, G., Pinelli, M., Musacchia, F., Mutarelli, M., Carrella, D., Vitiello, G., Capra, V., Parenti, G., Leuzzi, V., Selicorni, A., Maitz, S., Banfi, S., Zollino, Marcella, Montomoli, M., Milani, D., Romano, C., Tummolo, A., De Brasi, D., Coppola, A., Santoro, C., Peron, A., Pantaleoni, C., Castello, R., D'Arrigo, S., Sousa, S. B., Hennekam, R. C. M., Sadikovic, B., Thevenon, J., Govin, J., Vitobello, A., Zollino M. (ORCID:0000-0003-4871-9519), Cappuccio, G., Sayou, C., Tanno, P. L., Tisserant, E., Bruel, A. -L., Kennani, S. E., Sa, J., Low, K. J., Dias, C., Havlovicova, M., Hancarova, M., Eichler, E. E., Devillard, F., Moutton, S., Van-Gils, J., Dubourg, C., Odent, S., Gerard, B., Piton, A., Yamamoto, T., Okamoto, N., Firth, H., Metcalfe, K., Moh, A., Chapman, K. A., Aref-Eshghi, E., Kerkhof, J., Torella, A., Nigro, V., Perrin, L., Piard, J., Le Guyader, G., Jouan, T., Thauvin-Robinet, C., Duffourd, Y., George-Abraham, J. K., Buchanan, C. A., Williams, D., Kini, U., Wilson, K., Brunetti-Pierri, N., Casari, G., Pinelli, M., Musacchia, F., Mutarelli, M., Carrella, D., Vitiello, G., Capra, V., Parenti, G., Leuzzi, V., Selicorni, A., Maitz, S., Banfi, S., Zollino, Marcella, Montomoli, M., Milani, D., Romano, C., Tummolo, A., De Brasi, D., Coppola, A., Santoro, C., Peron, A., Pantaleoni, C., Castello, R., D'Arrigo, S., Sousa, S. B., Hennekam, R. C. M., Sadikovic, B., Thevenon, J., Govin, J., Vitobello, A., and Zollino M. (ORCID:0000-0003-4871-9519)

Abstract

Purpose: Nontruncating variants in SMARCA2, encoding a catalytic subunit of SWI/SNF chromatin remodeling complex, cause Nicolaides–Baraitser syndrome (NCBRS), a condition with intellectual disability and multiple congenital anomalies. Other disorders due to SMARCA2 are unknown. Methods: By next-generation sequencing, we identified candidate variants in SMARCA2 in 20 individuals from 18 families with a syndromic neurodevelopmental disorder not consistent with NCBRS. To stratify variant interpretation, we functionally analyzed SMARCA2 variants in yeasts and performed transcriptomic and genome methylation analyses on blood leukocytes. Results: Of 20 individuals, 14 showed a recognizable phenotype with recurrent features including epicanthal folds, blepharophimosis, and downturned nasal tip along with variable degree of intellectual disability (or blepharophimosis intellectual disability syndrome [BIS]). In contrast to most NCBRS variants, all SMARCA2 variants associated with BIS are localized outside the helicase domains. Yeast phenotype assays differentiated NCBRS from non-NCBRS SMARCA2 variants. Transcriptomic and DNA methylation signatures differentiated NCBRS from BIS and those with nonspecific phenotype. In the remaining six individuals with nonspecific dysmorphic features, clinical and molecular data did not permit variant reclassification. Conclusion: We identified a novel recognizable syndrome named BIS associated with clustered de novo SMARCA2 variants outside the helicase domains, phenotypically and molecularly distinct from NCBRS.

Published
2020

13. Mowat–Wilson Syndrome: Facial Phenotype Changing With Age: Study of 19 Italian Patients and Review of the Literature

Author

Garavelli, L., Zollino, M., Mainardi, Cerruti P., Gurrieri, F., Rivieri, F., Soli, F., Verri, R., Albertini, E., Favaron, E., Zignani, M., Orteschi, D., Bianchi, P., Faravelli, F., Forzano, F., Seri, M., Wischmeijer, A., Turchetti, D., Pompilii, E., Gnoli, M., Cocchi, G., Mazzanti, L., Bergamaschi, R., De Brasi, D., Sperandeo, M. P., Mari, F., Uliana, V., Mostardini, R., Cecconi, M., Grasso, M, Sassi, S., Sebastio, G., Renieri, A., Silengo, M., Bernasconi, S., Wakamatsu, N., and Neri, G.

Published
2009
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16. Use of narrative medicine to identify key factors for effective doctor–patient relationships in severe asthma

Author

Cappuccio, A., Napolitano, S., Menzella, F., Pellegrini, G., Policreti, A., Pelaia, G., Porpiglia, P. A., Marini, M. G., Antonelli, A., Arezzo, C., Baglioni, S., Boni, E., Bragantini, A., Bruzzese, D., Caldarelli, V., Caminati, M., Caminiti, L., Carraro, C., Ceccon, M. A., Bianchi, F. C., Cirisano, A., Cogo, R., Conte, E., D(')Auria, E., Daniele, S., De Brasi, D., De Castro, G., De Luca, S., Detoraki, C., Di Palmo, E., Fenu, G., Ferrara, A., Ferrigno, G., Fusi, A., Gaccione, A., Gandino, M., Guarnieri, G., Guerrieri, A., Iacoacci, C., Lacedonia, D., Schiavo, M. L., Longo, R., Magazz(`u), C., Marzo, G., Mastroberardino, M., Mattioli, G. P., Monaco, L., Montera, C., Morelli, M., Nicolini, A., Omodeo, P., Palmiero, G., Pannofino, A., Papa, A., Patria, F., Pini, L., Polti, S., Pontillo, A., Poppa, M., Poto, S., Quercia, O., Raie, A., Ronzoni, V., Rosati, Y., Russo, A., Salzillo, A., Santoro, M., Savoia, F., Simonazzi, A., Sposato, B., Tourtchenko, V., Tripodi, S., Vatrella, A., and Veronelli, E.

Subjects
Pulmonary and Respiratory Medicine, Severe asthma, medicine.medical_specialty, media_common.quotation_subject, Medical education and training, Empathy, Grounded theory, 03 medical and health sciences, 0302 clinical medicine, Promotion (rank), Qualitative research, Medicine, Narrative, Original Research Article, 030212 general & internal medicine, education, Asthma, media_common, lcsh:RC705-779, Narrative medicine, education.field_of_study, business.industry, lcsh:Diseases of the respiratory system, medicine.disease, 030228 respiratory system, Family medicine, business
Abstract

Background: In this project the authors use a narrative medicine (NM) approach to assess the promotion of trust in the relationship between physicians and their asthma patients. Methods: Following a NM educational course for physicians, a research was carried out in which at least 5 written narratives (parallel charts) for each participating physician were collected and qualitatively analysed according to Bury’s classification and the Grounded Theory. Results: The results of this study were of speculative and clinical interest. In particular, 66 participants wrote 314 narratives (246 on adult and 68 on paediatric patients). As a result of applying the NM approach, when the relationships remained problematic, many physicians wrote with a moral style about their adult (67%), and paediatric patients (33%) - especially in cases of asthmatic children’s or adolescents’ overprotective or absent families (40%) -. On the contrary, physicians who were able to listen to their patients with empathy (35%) made more shared decisions with patients, even with those they initially had a bad relationship. The used words of welcome, interest and acceptance were promoting patients’ trust that lead to restoring their activities in 45% of cases, according to physicians self-reporting. Conclusions: These approaches of NM are useful in daily clinical practice, with the goal of improving the quality of life (QOL) of patients with severe asthma, even in cases in which the doctor-patient relationship isn’t initially good.

Published
2019

20. Phenotype and genotype of 87 patients with Mowat–Wilson syndrome and recommendations for care

Author

Ivanovski, I. (Ivan), Djuric, O. (Olivera), Caraffi, S.G. (Stefano Giuseppe), Santodirocco, D. (Daniela), Pollazzon, M. (Marzia), Rosato, S. (Simonetta), Cordelli, D.M. (Duccio M.), Abdalla, E. (Ebtesam), Accorsi, P. (Patrizia), Adam, M.P. (Margaret), Ajmone, P.F. (Paola Francesca), Badura-Stronka, M. (Magdalena), Baldo, C. (Chiara), Baldi, M. (Maddalena), Bayat, A. (Allan), Bigoni, S. (Stefania), Bonvicini, F. (Federico), Breckpot, J. (Jeroen), Callewaert, L., Cocchi, G. (Guido), Cuturilo, G. (Goran), De Brasi, D. (Daniele), Devriendt, K. (Koenraad), Dinulos, M.B. (Mary Beth), Hjortshøj, T.D. (Tina Duelund), Epifanio, R. (Roberta), Faravelli, F. (Francesca), Fiumara, A. (Agata), Formisano, D. (Debora), Giordano, L. (Lucio), Grasso, M. (Marina), Grønborg, S. (Sabine), Iodice, A. (Alessandro), Iughetti, L. (Lorenzo), Kuburovic, V. (Vladimir), Kutkowska-Kazmierczak, A. (Anna), Lacombe, D. (Didier), Lo Rizzo, C. (Caterina), Luchetti, A. (Anna), Malbora, B. (Baris), Mammi, I. (Isabella), Mari, F. (Francesca), Montorsi, G. (Giulia), Moutton, S. (Sebastien), Møller, R.S. (Rikke), Muschke, P. (Petra), Nielsen, J.E.K. (Jens Erik Klint), Obersztyn, E. (Ewa), Pantaleoni, C. (Chiara), Pellicciari, A. (Alessandro), Pisanti, M.A. (Maria Antonietta), Prpic, I. (Igor), Poch-Olive, M.L. (Maria Luisa), Raviglione, F. (Federico), Renieri, A. (Alessandra), Ricci, E. (Emilia), Rivieri, F. (Francesca), Santen, G.W.E. (Gijs), Savasta, S. (Salvatore), Scarano, G. (Gioacchino), Schanze, I. (Ina), Selicorni, A. (Angelo), Silengo, M.C., Smigiel, R. (Robert), Spaccini, L. (Luigina), Sorge, G. (Giovanni), Szczaluba, K. (Krzysztof), Tarani, L. (Luigi), Tone, L.G. (Luis Gonzaga), Toutain, A. (Annick), Trimouille, A. (Aurelien), Valera, E.T. (Elvis Terci), Vergano, S.S. (Samantha Schrier), Zanotta, N. (Nicoletta), Zenker, M. (Martin), Conidi, A. (Andrea), Zollino, M., Rauch, A., Zweier, C. (Christiane), Garavelli, L. (Livia), Ivanovski, I. (Ivan), Djuric, O. (Olivera), Caraffi, S.G. (Stefano Giuseppe), Santodirocco, D. (Daniela), Pollazzon, M. (Marzia), Rosato, S. (Simonetta), Cordelli, D.M. (Duccio M.), Abdalla, E. (Ebtesam), Accorsi, P. (Patrizia), Adam, M.P. (Margaret), Ajmone, P.F. (Paola Francesca), Badura-Stronka, M. (Magdalena), Baldo, C. (Chiara), Baldi, M. (Maddalena), Bayat, A. (Allan), Bigoni, S. (Stefania), Bonvicini, F. (Federico), Breckpot, J. (Jeroen), Callewaert, L., Cocchi, G. (Guido), Cuturilo, G. (Goran), De Brasi, D. (Daniele), Devriendt, K. (Koenraad), Dinulos, M.B. (Mary Beth), Hjortshøj, T.D. (Tina Duelund), Epifanio, R. (Roberta), Faravelli, F. (Francesca), Fiumara, A. (Agata), Formisano, D. (Debora), Giordano, L. (Lucio), Grasso, M. (Marina), Grønborg, S. (Sabine), Iodice, A. (Alessandro), Iughetti, L. (Lorenzo), Kuburovic, V. (Vladimir), Kutkowska-Kazmierczak, A. (Anna), Lacombe, D. (Didier), Lo Rizzo, C. (Caterina), Luchetti, A. (Anna), Malbora, B. (Baris), Mammi, I. (Isabella), Mari, F. (Francesca), Montorsi, G. (Giulia), Moutton, S. (Sebastien), Møller, R.S. (Rikke), Muschke, P. (Petra), Nielsen, J.E.K. (Jens Erik Klint), Obersztyn, E. (Ewa), Pantaleoni, C. (Chiara), Pellicciari, A. (Alessandro), Pisanti, M.A. (Maria Antonietta), Prpic, I. (Igor), Poch-Olive, M.L. (Maria Luisa), Raviglione, F. (Federico), Renieri, A. (Alessandra), Ricci, E. (Emilia), Rivieri, F. (Francesca), Santen, G.W.E. (Gijs), Savasta, S. (Salvatore), Scarano, G. (Gioacchino), Schanze, I. (Ina), Selicorni, A. (Angelo), Silengo, M.C., Smigiel, R. (Robert), Spaccini, L. (Luigina), Sorge, G. (Giovanni), Szczaluba, K. (Krzysztof), Tarani, L. (Luigi), Tone, L.G. (Luis Gonzaga), Toutain, A. (Annick), Trimouille, A. (Aurelien), Valera, E.T. (Elvis Terci), Vergano, S.S. (Samantha Schrier), Zanotta, N. (Nicoletta), Zenker, M. (Martin), Conidi, A. (Andrea), Zollino, M., Rauch, A., Zweier, C. (Christiane), and Garavelli, L. (Livia)

Abstract

Purpose: Mowat–Wilson syndrome (MWS) is a rare intellectual disability/multiple congenital anomalies syndrome caused by heterozygous mutation of the ZEB2 gene. It is generally underestimated because its rarity and phenotypic variability sometimes make it difficult to recognize. Here, we aimed to better delineate the phenotype, natural history, and genotype–phenotype correlations of MWS. Methods: In a collaborative study, we analyzed clinical data for 87 patients with molecularly confirmed diagnosis. We described the prevalence of all clinical aspects, including attainment of neurodevelopmental milestones, and compared the data with the various types of underlying ZEB2 pathogenic variations. Results: All anthropometric, somatic, and behavioral features reported here outline a variable but highly consistent phenotype. By presenting the most comprehensive evaluatio

Published
2018
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21. Phenotype and genotype of 87 patients with Mowat-Wilson syndrome and recommendations for care

Author

Ivanovski, I, Djuric, O, Caraffi, SG, Santodirocco, D, Pollazzon, M, Rosato, S, Cordelli, D M, Abdalla, E, Accorsi, P, Adam, MP, Ajmone, PF, Badura-Stronka, M, Baldo, C, Baldi, M, Bayat, A, Bigoni, S, Bonvicini, F, Breckpot, J, Callewaert, B, Cocchi, G, Cuturilo, G, De Brasi, D, DeVriendt, K, Dinulos, MB, Hjortshoj, TD, Epifanio, R, Faravelli, F, Fiumara, A, Formisano, D, Giordano, L, Grasso, M, Gronborg, S, Iodice, A, Iughetti, L, Kuburovic, V, Kutkowska-Kazmierczak, A, Lacombe, D, Lo Rizzo, C, Luchetti, A, Malbora, B, Mammi, I, Mari, F, Montorsi, G, Moutton, S, Moller, RS, Muschke, P, Nielsen, JEK, Obersztyn, E, Pantaleoni, C, Pellicciari, A, Pisanti, MA, Prpic, I, Poch-Olive, ML, Raviglione, F, Renieri, A, Ricci, E, Rivieri, F, Santen, GW, Savasta, S, Scarano, G, Schanze, I, Selicorni, A, Silengo, M, Smigiel, R, Spaccini, L, Sorge, G, Szczaluba, K, Tarani, L, Tone, LG, Toutain, A, Trimouille, A, Valera, ET, Vergano, SS, Zanotta, N, Zenker, M, Conidi, Andrea, Zollino, M, Rauch, A, Zweier, C, Garavelli, L, Ivanovski, I, Djuric, O, Caraffi, SG, Santodirocco, D, Pollazzon, M, Rosato, S, Cordelli, D M, Abdalla, E, Accorsi, P, Adam, MP, Ajmone, PF, Badura-Stronka, M, Baldo, C, Baldi, M, Bayat, A, Bigoni, S, Bonvicini, F, Breckpot, J, Callewaert, B, Cocchi, G, Cuturilo, G, De Brasi, D, DeVriendt, K, Dinulos, MB, Hjortshoj, TD, Epifanio, R, Faravelli, F, Fiumara, A, Formisano, D, Giordano, L, Grasso, M, Gronborg, S, Iodice, A, Iughetti, L, Kuburovic, V, Kutkowska-Kazmierczak, A, Lacombe, D, Lo Rizzo, C, Luchetti, A, Malbora, B, Mammi, I, Mari, F, Montorsi, G, Moutton, S, Moller, RS, Muschke, P, Nielsen, JEK, Obersztyn, E, Pantaleoni, C, Pellicciari, A, Pisanti, MA, Prpic, I, Poch-Olive, ML, Raviglione, F, Renieri, A, Ricci, E, Rivieri, F, Santen, GW, Savasta, S, Scarano, G, Schanze, I, Selicorni, A, Silengo, M, Smigiel, R, Spaccini, L, Sorge, G, Szczaluba, K, Tarani, L, Tone, LG, Toutain, A, Trimouille, A, Valera, ET, Vergano, SS, Zanotta, N, Zenker, M, Conidi, Andrea, Zollino, M, Rauch, A, Zweier, C, and Garavelli, L

Published
2018

23. Adherence to guidelines for management of children hospitalized for acute diarrhea

Author

Lo Vecchio, A, Liguoro, I, Bruzzese, D, Scotto, R, Parola, L, Gargantini, G, Guarino, A, Accreditation, Quality Improvement Working Group of Italian Society of Pediatrics Kosova, P, Di Benedetto, L, Gattinara, Gc, Cursi, L, Parmigiani, S, Maddaluno, S, Campa, A, Caroccia, C, Adamoli, P, Forchì, G, Di Bari, C, Daniele, Rm, Saitta, F, Di Fraia, T, Bellettato, M, Meneghini, A, Principi, N, Esposito, S, Borgna, C, Fiumana, E, Zanconato, S, Masiero, S, Paravati, F, Pacenza, C, Cherubini, S, Frasca, D, Siani, P, De Brasi, D, Montrasio, G, Parolo, E, Podestà, Af, Tonella, M, Longhi, R, Ortisi, Mt, Rondanini, G, Calzi, P, Zucchinetti, P, Insolvibile, A, Navone, C, Ventura, F, Parisi, G, Isolato, V, Martemucci, L, D'Avino, P, Vetrano, G, Limongelli, Mg, Icilio, D, Muccioli, R., COLELLA, Maria Grazia, PACE, Maria Caterina, PERRONE, Laura, CAPRISTO, Carlo, Lo Vecchio, A, Liguoro, I, Bruzzese, D, Scotto, R, Parola, L, Gargantini, G, Guarino, A, Accreditation, Quality Improvement Working Group of Italian Society of Pediatrics Kosova, P, Di Benedetto, L, Gattinara, Gc, Cursi, L, Parmigiani, S, Maddaluno, S, Campa, A, Caroccia, C, Adamoli, P, Forchì, G, Di Bari, C, Daniele, Rm, Saitta, F, Di Fraia, T, Bellettato, M, Meneghini, A, Principi, N, Esposito, S, Borgna, C, Fiumana, E, Zanconato, S, Masiero, S, Paravati, F, Pacenza, C, Colella, Maria Grazia, Cherubini, S, Frasca, D, Siani, P, De Brasi, D, Montrasio, G, Parolo, E, Podestà, Af, Tonella, M, Longhi, R, Ortisi, Mt, Rondanini, G, Calzi, P, Zucchinetti, P, Insolvibile, A, Navone, C, Ventura, F, Parisi, G, Isolato, V, Pace, Maria Caterina, Martemucci, L, D'Avino, P, Vetrano, G, Limongelli, Mg, Perrone, Laura, Capristo, Carlo, Icilio, D, Muccioli, R., LO VECCHIO, Andrea, Bruzzese, Dario, and Guarino, Alfredo

Subjects
Diarrhea, Male, Microbiological Techniques, Microbiology (medical), Acute diarrhea, medicine.medical_specialty, Psychological intervention, Guidelines, Health Services Misuse, Hospital, Internal medicine, medicine, Humans, Prospective Studies, Medical prescription, Child, Preschool, Antidiarrheals, Prospective cohort study, book, Pediatric gastroenterology, Adherence, Gastroenteritis, Acute Disease, Anti-Bacterial Agents, Child, Preschool, Feeding Behavior, Female, Guideline Adherence, Hospitalization, Infant, Italy, Practice Guidelines as Topic, Probiotics, business.industry, Hepatology, Antidiarrheal Drugs, Infectious Diseases, Pediatrics, Perinatology and Child Health, Emergency medicine, Pediatric Infectious Disease, book.journal, business
Abstract

BACKGROUND: The major burden of acute gastroenteritis (AGE) in childhood is related to its high frequency and the large number of hospitalizations, medical consultations, tests and drug prescriptions. The adherence to evidence-based recommendations for AGE management in European countries is unknown. The purpose of the study was to compare hospital medical interventions for children admitted for AGE with recommendations reported in the European Societies of Pediatric Gastroenterology, Hepatology and Nutrition and Pediatric Infectious Diseases guidelines. METHODS: A multicenter prospective study was conducted in 31 Italian hospitals. Data on children were collected through an online clinical reporting form and compared with European Societies of Pediatric Gastroenterology, Hepatology and Nutrition and Pediatric Infectious Diseases guidelines for AGE. The main outcomes were the inappropriate hospital admissions and the percentage of compliance to the guidelines (full >90%, partial >80% compliance) based on the number and type of violations to evidence-based recommendations. RESULTS: Six-hundred and twelve children (53.6% male, mean age 22.8 ± 15.4 months) hospitalized for AGE were enrolled. Many hospital admissions (346/602, 57.5%) were inappropriate. Once admitted, 20.6% (126/612) of children were managed in full compliance with the guidelines and 44.7% (274/612) were managed in partial compliance. The most common violations were requests for microbiologic tests (404; 35.8%), diet changes (310; 27.6%) and the prescription of non-recommended probiotics (161; 14.2%), antibiotics (103; 9.2%) and antidiarrheal drugs (7; 0.6%). CONCLUSIONS: Inappropriate hospital admissions and medical interventions are still common in the management of children with AGE in Italy. Implementation of guidelines recommendations is needed to improve quality of care

Published
2014

33. Smith-Lemli-Opitz syndrome: evidence of T93M as a common mutation of D7-sterol reductase in Italy and report of three novel mutations

Author

DE BRASI D, ESPOSITO T, ROSSI M, SPERANDEO MP, ZUPPALDI A, BARDARO T, AMBRUZZI MA, ZELANTE L, CICCODICOLA A, SEBASTIO G, D\'URSO M. ANDRIA G., PARENTI, GIANCARLO, DE BRASI, D, Esposito, T, Rossi, M, Parenti, Giancarlo, Sperandeo, Mp, Zuppaldi, A, Bardaro, T, Ambruzzi, Ma, Zelante, L, Ciccodicola, A, Sebastio, G, and D\'Urso, M. ANDRIA G.

Abstract

The Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive disorder of cholesterol biosynthesis characterised by facial dysmorphisms, mental retardation and multiple congenital anomalies. SLOS is caused by mutations of the human Delta7-sterol reductase (DHCR7) gene and, so far, 19 different mutations have been described. Among these, mutations impairing the activity of the C-terminus appear to be the most severe. Here we report the mutational analysis of the DHCR7 gene in nine Italian SLOS patients. The T93M mutation, previously reported in one patient, results the most frequent one (7/18 alleles) in our survey. Furthermore, we identified three novel mutations, two missense mutations (N407Y and E448K), and a 33 bp deletion spanning part of exon 5 and the donor splice site of intron 5.

Published
1999

47. Smith-Lemli-Opitz syndrome: evidence of T93M as a common mutation of Δ7-sterol reductase in Italy and report of three novel mutations.

Author

De Brasi, D, Esposito, T, Rossi, M, Parenti, G, Sperandeo, M P, Zuppaldi, A, Bardaro, T, Ambruzzi, M A, Zelante, L, Ciccodicola, A, Sebastio, G, D'Urso, M, and Andria, G

Subjects
*STEROL hormones, *REDUCTONES, *CHOLESTEROL, *BIOSYNTHESIS
Abstract

The Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive disorder of cholesterol biosynthesis characterised by facial dysmorphisms, mental retardation and multiple congenital anomalies. SLOS is caused by mutations of the human Δ7-sterol reductase (DHCR7) gene and, so far, 19 different mutations have been described. Among these, mutations impairing the activity of the C-terminus appear to be the most severe. Here we report the mutational analysis of the DHCR7 gene in nine Italian SLOS patients. The T93M mutation, previously reported in one patient, results the most frequent one (7/18 alleles) in our survey. Furthermore, we identified three novel mutations, two missense mutations (N407Y and E448K), and a 33bp deletion spanning part of exon 5 and the donor splice site of intron 5. [ABSTRACT FROM AUTHOR]

Published
1999
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49. Risk of autoimmune diseases in patients with RASopathies: systematic study of humoral and cellular immunity

Author

Maria Siano, Pietro Strisciuglio, Valentina Pinna, Serena Cabaro, F. Di Candia, S. Sestito, D. Melis, D. De Brasi, Maria Alessio, Vittoria D'Esposito, Stefano Pagano, Pietro Formisano, Marco Tartaglia, Daniela Concolino, V. Marchetti, Giuseppe Perruolo, A. De Luca, Siano, M A, Marchetti, V, Pagano, S, Di Candia, F, Alessio, M, De Brasi, D, De Luca, A, Pinna, V, Sestito, S, Concolino, D, Tartaglia, M, Strisciuglio, P, D'Esposito, V, Cabaro, S, Perruolo, G, Formisano, P, and Melis, D

Subjects
medicine.medical_specialty, Cellular immunity, Inflammatory cytokine, Antigens, CD19, Autoimmunity, CD8 T cells, RASopathy, medicine.disease_cause, Autoimmune Disease, Gastroenterology, Autoimmune Diseases, Immune system, Psoriasis, Internal medicine, medicine, Humans, Pharmacology (medical), Genetics (clinical), Autoimmune disease, Immunity, Cellular, biology, business.industry, Research, Autoantibody, General Medicine, medicine.disease, Inflammatory cytokines, CD8 T cell, biology.protein, Medicine, Antibody, business, Human
Abstract

Background Abnormalities of the immune system are rarely reported in patients affected by RASopathies. Aim of the current study was to investigate the prevalence of immune system dysfunction in a cohort of patients affected by RASopathies. Study design A group of 69 patients was enrolled: 60 at the Federico II University, Naples, 7 at University Magna Graecia of Catanzaro, 2 at “Scuola Medica Salernitana”, Salerno. An age- and sex-matched control group was also enrolled. Autoimmune disorders were investigated according to international consensus criteria. Immune framework was also evaluated by immunoglobulin levels, CD3, CD4, CD8, CD19, CD56 lymphocyte subpopulations, autoantibodies levels and panel of inflammatory molecules, in both patients and controls. Results Frequent upper respiratory tract infections were recorded in 2 patients; pneumonia, psoriasis and alopecia in single patients. Low IgA levels were detected in 8/44 patients (18.18%), low CD8 T cells in 13/35 patients (37.14%). Anti-tg and anti-TPO antibodies were detected in 3/24 patients (12.5%), anti r-TSH in 2 cases (8.33%), all in euthyroidism. Serum IgA and CD8 levels were significantly lower in patients than in controls (p 0.00685; p 0.000656 respectively). All tested patients showed increased inflammatory molecules compared to controls. These findings may anticipate the detection of overt autoimmune disease. Conclusions Patients affected by RASopathies are at risk to develop autoimmune disorders. Routine screening for autoimmunity is recommended in patients with RASopathy.

Published
2021

50. Endocrine system involvement in patients with RASopathies: A case series

Author

M. A. Siano, R. Pivonello, M. Salerno, M. Falco, C. Mauro, D. De Brasi, A. Klain, S. Sestito, A. De Luca, V. Pinna, C. Simeoli, D. Concolino, Ciro Gabriele Mainolfi, T. Mannarino, P. Strisciuglio, M. Tartaglia, D. Melis, Siano, M. A., Pivonello, R., Salerno, M., Falco, M., Mauro, C., De Brasi, D., Klain, A., Sestito, S., De Luca, A., Pinna, V., Simeoli, C., Concolino, D., Mainolfi, C. G., Mannarino, T., Strisciuglio, P., Tartaglia, M., and Melis, D.

Subjects
Endocrinology, Diabetes and Metabolism, Research, Humans, autoimmunity, bone mineral density, CFC, RASopathies, vitamin D, Endocrine System
Abstract

Background and ObjectivesEndocrine complications have been described in patients affected by RASopathies but no systematic assessment has been reported. In this study, we investigate the prevalence of endocrine disorders in a consecutive unselected cohort of patients with RASopathies.Study Design72 patients with a genetically confirmed RASopathy (Noonan syndrome [NS], N=53; 29 LEOPARD syndrome [LS], N=2; cardiofaciocutaneous syndrome [CFCS], N=14; subjects showing co-occurring pathogenic variants in PTPN11 and NF1, N=3) and an age- and sex-matched healthy controls were included in the study. Endocrine system involvement was investigated by assessing the thyroid function, pubertal development, auxological parameters, adrenal function and bone metabolism.ResultsShort stature was detected in 40% and 64% of the NS and CFCS subcohorts, respectively. Patients showed lower Z-scores at DXA than controls (pConclusionsThe collected data demonstrate a high prevalence of thyroid autoimmunity, confirming an increased risk to develop autoimmune disorders both in NS and CFCS. Reduced BMD, probably associated to reduced physical activity and inflammatory cytokines, also occurs. These findings are expected to have implications for the follow-up and prevention of osteopenia/osteoporosis in both NS and CFCS.

Published
2022

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